General disorders and

pyrcxia*, fatigue, asthcnia,chest

bruising, haematoma, induration, rash ,

administration pain, injection pruritus , site site innammation, conditions erythema, discoloration,

tnJections1te nodule and pam, hacmorrhagc(at mjectionsite injection site), reactmn malaise,chills, (unspecified) catheter site

hemorrhage

Investigations weight decreased

*=rarely fatal cases have been reported

Description of selected adverse reactions Haematologic adverse reactions

IOJCCllOTI

necrosis (at injection site)

The most commonly reported(# 10%) haematological adverse reactions associated with azacitidine treatment include anaemia, thrombocytopenia, neutropenia, febrile neutropenia and leukopenia, and were usually Grade 3 or 4. There is a greater risk of these events occurring during the first 2 cycles, after which they occur with less frequency in patients with restoration of haematological function. Most haematological adverse reactions were managed by routine monitoring of complete blood counts and delaying azacitidine administration in the next cycle, prophylactic antibiotics and/or growth factor support (e.g. G-CSF) for neutropenia and transfusions for anaemia or thrombocytopenia as required. Infections Myelosuppression may lead to neutropenia and an increased risk of infection. Serious adverse reactions such as sepsis, including neutropenic sepsis, and pneumonia were reported in patients receiving azacitidine, some with a fatal outcome. Infections may be managed with the use of antiinfectives plus growth factor support (e.g. G-CSF) for neutropenia.

Bleeding Bleeding may occur with patients receiving azacitidine. Serious adverse reactions such as gastrointestinal haemorrhage and intracranial haemorrhage have been reported. Patients should be monitored for signs and symptoms of bleeding, particularly those with pre-existing or treatment related thrombocytopenia.

Hypersensitivity Serious hypersensitivity reactions have been reported in patients receiving azacitidine. In case of an anaphylactic-like reaction, treatment with azacitidine should be immediately discontinued and appropriate symptomatic treatment initiated.

Skin and subcutaneous tissue adverse reactions The majority of skin and subcutaneous adverse reactions were associated with the injection site. None of these adverse reactions led to discontinuation of azacitidine, or reduction of azacitidine dose in the pivotal studies. The majority of adverse reactions occurred during the first 2 cycles and tended to decrease with subsequent cycles. Subcutaneous adverse reactions such as injection site rash/inflammation/pruritus, rash, erythema and skin lesion may require management with concomitant medicinal products, such as antihistamines, corticosteroids and non-steroidal anti-inflammatory medicinal products (NSAIDs). These cutaneous reactions have to be distinguished from soft tissue infections, sometimes occurring at injection site. Soft tissue infections, including cellulitis and necrotising fasciitis in rare cases leading to death, have been reported with azacitidine in the post marketing setting.

Gastrointestinal adverse reactions The most commonly reported gastrointestinal adverse reactions associated with azacitidine treatment included constipation, diarrhoea, nausea and vomiting. These adverse reactions were managed symptomatically with anti­emetics for nausea and vomiting; anti-diarrhoeals for diarrhoea, and laxatives and/or stool softeners for constipation.

Renal adverse reactions Renal abnormalities, ranging from elevated serum creatinine and haematuria to renal tubular acidosis, renal failure and death were reported in patients treated with azacitidine.

Hepatic adverse reactions Patients with extensive tumour burden due to metastatic disease have been reported to experience hepatic failure, progressive hepatic coma and death during azacitidine treatment.

Cardiac events Data from a clinical trial allowing enrolment of patients with known history of cardiovascular or pulmonary disease showed a statistically significant increase in cardiac events in patients with newly diagnosed A ML treated with azacitidine.

Elderly population There is limited safety information available with azacitidine in patients #'85 years

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OVERDOSE One case of overdose with Azacitidine for Injection was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single IV dose of approximately 290 mglm

2

, almost 4 times the recommended starting dose. The events resolved without sequelae, and the correct dose was resumed the following day. In the event of overdosage, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for Azacitidine overdosage

PHARMACOLOGICAL PROPERTIES Pharmacodynamics Pharmacotherapeutic group Antineoplastic agent, pyrimidine analogues; ATC code: L0IBC07

Mechanism of Action Azacitidine is a pyrimidine nucleoside analog of cytidine. AZACITlDfNE is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnonnal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non­proliferating eel Is are relatively insensitive to azacitidine

Pharmacokinetics The pharmacokinetics of azacitidine were studied in 6 MOS patients following a single 75 mg/m1 subcutaneous (SC) dose and a single 75 mg/m2

intravenous (IV) dose. Azacitidine is rapidly absorbed after SC administration; the peak plasma azacitidine concentration of 750 ± 403 ng/ml occurred in 0.5 hour. The bioavailability of SC azacitidine relative to IV azacitidine is approximately 89%, based on area under the curve. Mean volume of distribution following IV dosing is 76 ± 26 L. Mean apparent SC clearance is 167 ±49 L/hourand mean half-life after SC administration is41 ± 8 minutes. The AUC and Cmax of SC administration of azacitidine in 21 patients with cancer were approximately dose proportional within the 25 to I 00 mglm

1 dose range. Multiple dosing at the recommended dose-regimen docs not result in drug accumulation Published studies indicate that urinary excretion is the primary route of elimination of azacitidine and its metabolites. Following IV administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for <I% of administered radioactivity over 3 days. Mean excretion of radioactivity in urine following SC administration of 14C-azacitidine was 50%. The mean elimination half-lives of total radioactivity (azacitidine and its metabolites) were similar after rv and SC administrations, about 4 hours.

INCOMPATIBILITIES This medicinal product must not be mixed with other medicinal products including 5% Dextrose solutions, Hespan, or solutions that contain bicarbonate. These solutions have the potential to increase the rate of degradation of Azacitidine and should therefore be avoided.

STORAGE CONDITION Store at a temperature not exceeding 25°C.

In Use Stability S.C. Suspension Stability: AZAC[TIDfNE reconstituted with non­refrigerated water for injection for subcutaneous administration may be stored for up to I hour at 25°C (77°F) or for up to S hours between 2°C and S°C (36°F and 46°F); when reconstituted with refrigerated (2°C - S°C, 36°F -46°F) water for injection, it may be stored for 22 hours between 2°C and S°C (36°F and 46°F).

I.V. Solution Stability: AZACITIDINE reconstituted for intravenous administration may be stored at 25°C (77°F), but administration must be completed within I hour of reconstitution.

INSTRUCTION FOR USE AND HANDLING Azacitidine is a cytotoxic drug. Follow applicable special handling and disposal procedures.

Instruction for S ubcutaneousAdministration ReconstituteAZACITIDINE aseptically with 4 mL sterile water for injection. Inject the diluent slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved. The suspension will be cloudy. The resulting suspension will contain azacitidine 25 mg/mL. Do not filter the suspension after reconstitution. Doing so could remove the active substance.

Preparation for Immediate Subcutaneous Administration: Doses greater than 4 ml should be divided equally into 2 syringes. The product may be held at room temperature for up to I hour, but must be administered within 1 hour after reconstitution.

Preparation for Delayed Subcutaneous Administration: The reconstituted product may be kept in the vial or drawn into a syringe. Doses greater than 4 mL should be divided equally into 2 syringes. The product must be refrigerated immediately. When AZACITIDINE is reconstituted using water for injection that has not been refrigerated, the reconstituted product may be

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held under refrigerated conditions (2°C - 8°C, 36°F - 46°F) for up to S hours. When AZACJTIDfNE is reconstituted using refrigerated (2°C - S°C, 36°F -46°F) water for injection, the reconstituted product may be stored under refrigerated conditions (2°C - S°C, 36°F - 46°F) for up to 22 hours. After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior lo administration.

Subcutaneous Administration To provide a homogeneous suspension, the contents of the dosing syringe must be re-suspended immediately prior to administration. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy suspension is achieved. AZACJTIDfNE suspension is administered subcutaneously. Doses greater than 4 mL should be divided equally into 2 syringes and injected into 2 separate sites. Rotate sites for each injection (thigh, abdomen, or upper arm). New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, red, or hard.

Instructions for Intravenous Administration Reconstitute the appropriate number of AZACITTDINE vials to achieve the desired dose. Reconstitute each vial with IO ml sterile water for injection. Vigorously shake or roll the vial until all solids are dissolved. The resulting solution will contain azacitidine 10 mg/mL. The solution should be clear. Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container pennit. Withdraw the required amount of AZACITIDfNE solution to deliver the desired dose and inject into a 50 -100 mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated Ringer's Injection.

Intravenous Administration AZACJTIDINE solution is administered intravenously. Administer the total dose over a period of IO - 40 minutes. The administration must be completed within I hour of reconstitution of theAZACJTIDINE vial.

EFFECT ON ABILITY TO DRIVE AND USE MACHINE Do not drive or use any tools or machines if you experience side effects, such as tiredness

PACKAGING Azacitidine for injection is supplied as a lyophilized powder in I 00 mg single­dose vials packaged in unit carton

MA HOLDER AND MANUFACTURER Getwell Pharmaceuticals 474 Udyog Vihar, Phase V Gurgaon 122016, Haryana, INDIA

10/2016

I f in doubt do not hesitate to seek advice from your doctor or phannacist

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Size : 290 x 220mm

G GETWELL

For the use of Registered Medical Practitioner or Hospital or a Laboratory only.

Azacitidine for Injection 100mg

AZACITE™

Lyophilized Single Dose Vial

For Subcutaneous and Intravenous Use Only

Rx only

I WARNING I

• Anemia, Neutropenia and Thrombocytopenia: Monitor complete blood counts (CBC) frequently. • Hepatotoxicity: Patients with severe preexisting hepatic impairment are at higher risk for toxicity. • Renal Toxicity: Monitor patients with renal impairment for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys. • Tumor Lysis Syndrome: AZACITIDINE may cause fatal or serious tumor lysis syndrome, including in patients with MOS. Assess baseline risk and monitor and treat as appropriate. • Embryo-Fetal Risk: AZACITIDINE can cause fetal harm. Advise females with reproductive potential of the potential risk to a fetus and to avoid pregnancy.

DESCRIPTION Azacitidine for injection contains azacitidine, which is a pyrimidine nucleoside analog of cytidine. Azacitidine is 4-amino-1- p -D-ribofuranosyl­s-triazin-2( l H)-one. The structural formula is as follows·

The empirical formula is C8H12N405.The molecular weight is 244. Azacitidine is a white to offwhite solid. Azacitidine was found to be insoluble in acetone, ethanol, and methyl ethyl ketone; slightly soluble in ethanol/water (50/50), propylene glycol, and polyethylene glycol; sparingly soluble in water, water saturated octanol, 5% dextrose in water, N-methyl-2-pyrrolidone, normal saline and 5% Tween 80 in water; and soluble in dimethylsulfoxide (DMSO). The finished product is supplied in a sterile form for reconstitution as a suspension for subcutaneous injection or reconstitution as a solution with further dilution for intravenous infusion. Vials of Azacitidine for Injection contain I 00 mg of azacitidine and I 00 mg mannitol as a sterile lyophilized powder.

PHARMACEUTICAL FORM, DOSAGE AND ROUTE OF ADMINISTRATION

Pharmaceutical form: Lyophilized powder Dosage: I 00mg/vial Route of Administration: Subcutaneous or Intravenous

Each vial contains: Azacitidine Mannitol USP Water for Injection USP

COMPOSITION

100mg 100mg q.s.

THERAPEUTICE INDICATION Azacitidine is indicated for treatment of patients with the following French­American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation {RAEB-T), and chronic myelomonocytic leukemia (CMMoL).

DOSAGE AND METHOD OF ADMINISTRATION First Treatment Cycle The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m2

subcutaneously or intravenously, daily for 7 days. Premedicate patients for nausea and vomiting. Obtain complete blood counts, liver chemistries and

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